prostaglandin-d2 and Myocarditis

To test the hypothesis that activation of peroxisome proliferator activated receptor gamma (PPAR-gamma) reduces experimental autoimmune myocarditis (EAM) associated with inhibitor kappaB (IkappaB) alpha induction, blockade of nuclear factor kappaB (NF-kappaB), and inhibition of inflammatory cytokine expression.. EAM was induced in Lewis rats by immunisation with porcine cardiac myosin. PPAR-gamma activators 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2) and pioglitazone (PIO) were administered to rats with EAM.. Enhanced PPAR-gamma expression was prominently stained in the nuclear and perinuclear regions of infiltrating inflammatory cells. Administration of 15d-PGJ2 and PIO greatly reduced the severity of myocarditis and suppressed myocardial mRNA and protein expression of inflammatory cytokines in rats with EAM. In addition, treatment with PPAR-gamma activators enhanced IkappaB concentrations in the cytoplasmic fractions and nuclear fractions from inflammatory myocardium. Concurrently, NF-kappaB was greatly activated in myocarditis; this activation was blocked in the 15d-PGJ2 treated and PIO treated groups.. PPAR-gamma may have a role in the pathophysiology of EAM. Because an increase in IkappaB expression and inhibition of translocation of the NF-kappaB subunit p65 to the nucleus in inflammatory cells correlated with the protective effects of PPAR-gamma activators, these results suggest that PPAR-gamma activators act sequentially through PPAR-gamma activation, IkappaB induction, blockade of NF-kappaB activation, and inhibition of inflammatory cytokine expression. These results suggest that PPAR-gamma activators such as 15d-PGJ2 and PIO may have the potential to modulate human inflammatory heart diseases such as myocarditis.

Topics: Acute Disease; Animals; Autoimmune Diseases; Cardiotonic Agents; Cytokines; Gene Expression Regulation; Myocarditis; Myosins; NF-kappa B; Pioglitazone; PPAR gamma; Prostaglandin D2; Rats; Rats, Inbred Lew; RNA, Messenger; Thiazolidinediones

Recent evidence has suggested that peroxisome proliferator-activated receptor-gamma (PPAR-gamma) serves as a negative regulator in the immune system. In the present study, we investigated the expression of PPAR-gamma and the effect of PPAR-gamma ligands on experimental autoimmune myocarditis (EAM).. Experimental autoimmune myocarditis was induced in Lewis rats by immunization with porcine cardiac myosin. PPAR-gamma ligands 15-deoxy-Delta-PGJ2 200 microg x kg(-1) x d(-1) by ip and pioglitazone 10 mg x kg(-1) x d(-1) by oral were administered for 3 weeks. PPAR-gamma expression was upregulated in myocarditis and the enhanced PPAR-gamma expression was prominently stained in the nuclear and perinuclear regions of the positive-stained cells in the inflammatory lesions. Administration of PPAR-gamma ligands markedly reduced the severity of myocarditis, as indicated by the heart weight/body weight ratio, pericardial effusion scores, macroscopic scores, and microscopic scores. The upregulated PPAR-gamma expression was also reduced by PPAR-gamma ligands treatment. In addition, PPAR-gamma ligands suppressed the proliferative response and interferon-gamma production of T cell-enriched splenocytes from rats with EAM. Furthermore, the cytotoxic activity and myocarditogenic potential of these T cells were inhibited by PPAR-gamma ligands treatment.. PPAR-gamma ligands ameliorate EAM associated with inhibition of expansion and activation of the self-sensitive T cells. These results suggest that PPAR-gamma ligands may have the potential to modulate human inflammatory heart diseases as myocarditis.

Topics: Animals; Autoimmune Diseases; Cells, Cultured; Dose-Response Relationship, Drug; Ligands; Myocarditis; Myocytes, Cardiac; Pioglitazone; Prostaglandin D2; Rats; Rats, Inbred Lew; Receptors, Cytoplasmic and Nuclear; Swine; T-Lymphocytes; Thiazolidinediones; Transcription Factors

Topics: Animals; Autoimmune Diseases; Cytokines; Immunohistochemistry; Ligands; Myocarditis; NF-kappa B; PPAR gamma; Prostaglandin D2; Rats; Rats, Inbred Lew

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands have been shown to ameliorate a variety of inflammatory conditions. The present study tested the hypothesis that PPAR-gamma ligands reduce experimental autoimmune myocarditis (EAM) associated with inhibition of the expansion and activation of T cells, as well as suppression of the expression of proinflammatory cytokines.. EAM was induced in Lewis rats by immunization with porcine cardiac myosin. PPAR-gamma ligands, 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) 200 microg/kg/day i.p. and pioglitazone (PIO) 10 mg/kg/day orally, were administered for 3 weeks to rats with EAM. The results showed that enhanced PPAR-gamma expression was prominently stained in the nuclear and perinuclear regions of infiltrating inflammatory cells. Administration of PPAR-gamma ligands markedly reduced the severity of myocarditis, as shown by comparing the heart weight/body weight ratio, pericardial effusion scores, macroscopic scores and microscopic scores. PPAR-gamma ligands suppressed myocardial mRNA expression of inflammatory cytokines and the expression of interleukin (IL)-1beta protein in rats with EAM. In addition, 15d-PGJ(2) and PIO treatment suppressed the proliferative response and interferon-gamma production of T cell-enriched splenocytes from rats with EAM. Furthermore, the cytotoxic activity and myocardiogenic potential of these T cells were inhibited by 15d-PGJ(2) treatment.. PPAR-gamma may play a role in the pathophysiology of EAM. PPAR-gamma ligands ameliorate the EAM associated with suppression of the expansion and activation of myocardiogenic T cells, as well as inhibition of the expression of proinflammatory cytokines. These results suggest that PPAR-gamma ligands such as 15d-PGJ(2) and PIO may have the potential to modulate human inflammatory heart diseases such as myocarditis.

Topics: Animals; Autoimmune Diseases; Hypoglycemic Agents; Interleukin-1; Models, Animal; Myocarditis; Pioglitazone; Prostaglandin D2; Rats; Rats, Inbred Lew; Receptors, Cytoplasmic and Nuclear; Thiazolidinediones; Transcription Factors

To investigate the role of peroxisome proliferator-activated receptor-gamma (PPAR gamma) on autoimmune myocarditis, and to test the hypothesis that PPAR-gamma ligands reduce experimental autoimmune myocarditis (EAM) associated with inhibition of the expansion and activation of self-sensitive T cells.. EAM was induced in Lewis rats by immunization with porcine cardiac myosin. Then the rats were divided into 3 groups of 9 rats: PPAR-gamma ligand 15-deoxy-(12,14)-PGJ(2) (15d-PGJ(2)) group (15d-PGJ(2) was injected intraperitoneally at the dosage of 200 microg.kg(-1).d(-1)), pioglitazone (PIO) group (PIO was mixed with the food and than fed at the dosage of 10 mg.kg(-1).d(-1)), and positive control group (phosphate-buffered saline was injected intraperitoneally). Nine normal rats were used as normal controls. Three weeks later, the rats underwent thoracotomy to undergo pathologic examination. The numbers of CD4(+) cells, CD8(+) cells, and macrophages were calculated by microscopy. Immunohistochemistry was used to examine the location and expression of PPAR gamma. Western blotting was used to examine the relative amount of PPAR gamma protein. The proliferative response and the cytotoxicity of T cell-enriched splenocytes and lymph node cells were determined. Another rats were killed 12 days after immunization. Their spleens and lymph nodes were taken out. T-cell rich splenocytes and cells from the lymph nodes were cultured. Cardiac myosin and 15d-PGJ(2) were added. [(3)H] thymine was added 72 hours after. ELISA was used to examine the interferon-gamma (IFN-gamma) in the supernatant. 15d-PGJ(2), PIO, or PBS were given to immunize the rats. The rats were killed 12 days after. The lymph nodes were taken out to make single cell suspension. (51)Cr was used to label the cells so as to calculate the %cytotoxicity.. All immunized rats showed myocarditis. The numbers of CD4(+) cells, CD8(+) T cells, and macrophages, were 18 +/- 5, 7 +/- 2, and 45 +/- 8/six 0.25 mm x 0.25 mm squares. PPAR gamma was mainly located in the nuclear and perinuclear regions of infiltrating inflammatory cells, such as mononuclear cells and macrophage-like cells. The expression of PPAR gamma in the myocardium of EAM rats was 3.7 times higher than of the normal rats. The heart weight/body weight ratio, pericardial effusion scores, macroscopic scores and microscopic scores of the 15d-PGJ group were significantly lower than those of the positive control group. The numbers of CD4(+) cells of the 15d-PGJ and PIO groups were 8 +/- 2 and 10 +/- 3, both significantly lower than that of the positive control group (both P < 0.01), the numbers of CD8(+) cells of the 15d-PGJ and PIO groups were 3 +/- 1 and 4 +/- 2 respectively, both significantly lower than that of the positive control group (P < 0.01 and P < 0.05), and the numbers of macrophages of the 15d-PGJ and PIO groups were 22 +/- 4 and 26 +/- 6 respectively, both significantly lower than that of the positive control group (both P < 0.01). The myocardiogenicity and the severity of myocarditis of the 15d-PGJ(2)- and PIO-groups were at lower degrees compared with those of the positive control group. The % cytotoxic activity was 10.2% +/- 2.6% in the 15d-PGJ(2) group and was 11.6% +/- 3.7% in the PIO group, both significantly lower than that of the positive control group (37.7% +/- 8.4%, both P < 0.01) Stimulated by cardiac myosin, the T-cell rich splenocytes and cells from lymph nodes showed obvious proliferation and production of IFN-gamma. The cardiac myosin-stimulated cell proliferation and production of IFN-gamma in the 15d-PGJ(2) and PIO groups were significantly reduced in comparison with those in the positive control group.. PPAR-gamma ligands ameliorate EAM associated with inhibition of expansion and activation of the self-sensitive T cells.

Topics: Animals; Autoimmune Diseases; Immunosuppressive Agents; Myocarditis; Pioglitazone; Prostaglandin D2; Rats; Rats, Inbred Lew; Receptors, Cytoplasmic and Nuclear; Swine; T-Lymphocytes; Thiazolidinediones; Transcription Factors